In general, WS cells have a high level of genomic instability, with increased amounts of DNA deletions, insertions, and rearrangements. These effects could potentially be the result of defects in DNA repair, replication, and/or recombination, although the actual biochemical defect remains unknown. WRN protein possesses both helicase and exonuclease functions. Using a large screen, we identified small molecule inhibitors for WRNs catalytic activities that can be used to explore its biological activities in vivo. The laboratory also continues to investigate the localization of WRN to sites of DNA damage using site directed mutagenesis of critical amino acids in WRN protein combined with confocal microscopy. Our findings show that basic residues are important for its localization and that amino acids modified by posttranslational modifications can modulate WRNs re-localization to sites of DNA and retention times there. NAD depletion has been implicated in several hallmarks of aging. Given that WRN syndrome is the best described premature aging syndrome, we have been investigating the use of NAD replenishment strategies to offset WRN-dependent pathologies. We found lower NAD and mitophagy levels in WRN-deficient patients and worm models. We showed that WRN specifically regulates expression of a key NAD biosynthetic enzyme, NMNAT1. Additionally, we reported that NAD supplementation can rescue lifespan in both WRN syndrome fly and worm models. These results contribute to the growing body of literature demonstrating that NAD supplementation can offset features of aging in part through improved mitochondrial function.